The corneal epithelium is the main protective barrier for the cornea, and complete restoration of the corneal epithelium following trauma or surgery is essential for the restitution of normal visual function. The mechanism(s) and factors responsible for the maintenance and repair of the corneal epithelium are unclear. We have discovered that an endogenous opioid system (EOS) modulates rabbit corneal epithelial explant outgrowth, re-epithelialization in culture and in vivo, and homeostasis. Moreover, both the opioid growth factor (OGF), [Met/5]-enkephalin, and its receptor, zeta, are present in the basal and suprabasal cells of the corneal epithelium of humans and animals. OGF is a native, tonically active, inhibitory growth factor that is targeted to growth-related events. Blockage of OGF action using opioid antagonists such as naltrexone (NTX), dramatically stimulates the proliferation and migration of corneal epithelial cells in explants, re-epithelialization in organ culture and in vivo, and DNA synthesis of epithelial and limbal cells. This grant explores the hypothesis that an EOS plays a role in the maintenance and restitution of the corneal epithelium. Specific aims include: (1) Define the presence and location of OGF, mRNA for OGF hormone (preproenkephalin), zeta receptor, and OGF binding sites in the epithelium, limbus, and conjunctiva of normal cornea. (2) Examine the presence, response, and function of the EOS in rabbit cornea in vivo during injury and repair. The relationship of EOS to cell proliferation, migration, and differentiation, and re-epithelialization and healing, will be established. Paradigms using excess OGF and blockade of OGF-receptor interaction will be employed to understand EOS function. (3) Elucidate the influence of EOS on homeostasis of rabbit cornea. (4) Study the influence of EOS in human corneal epithelium on cell proliferation, migration, and differentiation, as well as cell/tissue organization, utilizing explants. (5) Ascertain the biology of EOS in human corneal epithelium, limbus, and conjunctiva during maintenance, injury, and re-epithelialization using an organ culture model. These studies are part of a long-range program directed towards understanding the pathogenesis and treatment of corneal diseases, particularly disorders of the corneal epithelium.